Introduction

Uses for Saquinavir

Treatment of HIV Infection

Treatment of HIV type 1 (HIV-1) infection in adults and adolescents >16 years of age;1200201 used in conjunction with low-dose ritonavir (ritonavir-boosted saquinavir) and other antiretrovirals.1174179200201300

Do not use saquinavir without a pharmacokinetic enhancer (i.e., low-dose ritonavir).1200201 Pharmacokinetic enhancer (pharmacokinetic booster) necessary to improve saquinavir pharmacokinetic profile.1200 Do not use with the pharmacokinetic enhancer cobicistat.1 (See Interactions under Cautions.)

Ritonavir-boosted saquinavir usually used in PI-based regimens that include a PI and 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs).1200

Experts state ritonavir-boosted saquinavir not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents because of higher pill burden and more severe adverse cardiac effects (prolonged PR and QT intervals requiring ECG monitoring) compared with other available ritonavir-boosted PIs.200 (See Cardiovascular Effects under Cautions.) Experts also state not recommended for initial treatment regimens in antiretroviral-naive pediatric patients because of limited data.201

Use of saquinavir without low-dose ritonavir (unboosted saquinavir) not recommended at any time because of inadequate bioavailability and inferior virologic efficacy.200201

USPHS recommends a 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as the preferred regimen for PEP following occupational exposures to HIV.199Ritonavir-boosted saquinavir and 2 NRTIs can be considered an alternative regimen, but use for PEP only with expert consultation.199 Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF; alternatives are tenofovir DF and lamivudine, zidovudine and lamivudine, or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada);198 recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF.198

CDC states saquinavir is an alternative antiretroviral that can be used in nPEP regimens, but use in such regimens only with expert consultation.198

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals.198 Do not delay initiation of nPEP while waiting for expert consultation.198

Saquinavir Dosage and Administration

Administration

Oral Administration

Administer orally with low-dose ritonavir (ritonavir-boosted saquinavir) within 2 hours of a meal.11551

Administer saquinavir dose at same time as ritonavir dose.1 In patients already receiving ritonavir as part of an antiretroviral regimen, no additional ritonavir is needed.1

For patients unable to swallow capsules, empty contents of appropriate number of saquinavir capsules into container and mix with 15 mL of sugar syrup, 15 mL of sorbitol syrup, or 3 teaspoons of jam.1 Stir mixture for 30–60 seconds.1 Allow mixture to reach room temperature and administer entire dose to the patient.1

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT interval; torsades de pointes reported rarely.1 Perform ECG prior to initiation of ritonavir-boosted saquinavir.1 Do not use in patients with QT interval ≥450 msec.1Ritonavir-boosted saquinavir may be initiated in those with baseline QT interval <450 msec; however, repeat ECG after approximately 10 days of ritonavir-boosted saquinavir and discontinue the antiretroviral if QT interval is prolonged >20 msec over baseline.1 ECG monitoring recommended if ritonavir-boosted saquinavir is initiated in patients with CHF, bradyarrhythmias, hepatic impairment, and electrolyte abnormalities.1 Correct hypokalemia or hypomagnesemia prior to initiating ritonavir-boosted saquinavir; monitor these electrolytes periodically during therapy.1

Do not use ritonavir-boosted saquinavir concomitantly with drugs that increase saquinavir plasma concentrations and prolong QT interval.1 Manufacturer states that concomitant use of ritonavir-boosted saquinavir and drugs with the potential to increase QT interval should be considered only when no alternative therapy is available and potential benefits outweigh risks.1 Perform ECG prior to initiation of the drugs.1 Do not use such concomitant therapy in patients with QT interval >450 msec.1 If baseline QT interval is <450 msec, repeat ECG after 3–4 days of concomitant therapy.1 If QT interval is prolonged >20 msec over baseline, clinician should use best clinical judgement regarding discontinuing ritonavir-boosted saquinavir and/or the other drug.1 Cardiology consult recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.1

Interactions

Saquinavir must be used with a pharmacokinetic enhancer (i.e., low-dose ritonavir).1 Failure to administer saquinavir with recommended dosage of low-dose ritonavir may result in inadequate antiretroviral effects.1200 When ritonavir-boosted saquinavir is used, consider cautions, precautions, contraindications, and drug interactions associated with both saquinavir and low-dose ritonavir.1

Do not use saquinavir with the pharmacokinetic enhancer cobicistat.1 Cobicistat is not interchangeable with low-dose ritonavir and dosage recommendations for concomitant use of saquinavir and cobicistat not established.1

Concomitant use of ritonavir-boosted saquinavir with certain drugs is not recommended or requires particular caution.1200 (See Specific Drugs and Foods under Interactions.)

Consider potential drug interactions prior to and during use of ritonavir-boosted saquinavir;1 monitor for adverse effects associated with each drug.1

Hyperglycemic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus reported with use of HIV PIs; diabetic ketoacidosis has occurred.1129131

Monitor blood glucose and initiate or adjust dosage of oral hypoglycemic agent or insulin as needed.1

Hepatic Effects

Exacerbation of chronic liver dysfunction reported in patients with HBV or HCV, cirrhosis, or other underlying liver abnormalities.1 (See Hepatic Impairment under Cautions.)

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution;1 time to onset is variable and can occur many months after initiation of antiretroviral therapy.1

HIV Resistance

Possibility of HIV-1 resistant to saquinavir and possible cross-resistance to other HIV PIs.1 Continued saquinavir therapy following loss of viral suppression may increase likelihood of cross-resistance to other HIV PIs.1

Lactation

Distributed into milk in rats;202 not known whether distributed into human milk.1202

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1202

Pediatric Use

Dosages of ritonavir-boosted saquinavir that are effective for treatment of HIV-1 infection in children <16 years of age and below threshold for corrected QT (QTc) and PR interval prolongation not identified to date.1

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1

Use caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Contraindicated in severe hepatic impairment.1 Although usual dosage can be used in mild or moderate hepatic impairment,1 some experts recommend caution.200

Interactions for Saquinavir

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A with possible alteration in metabolism of saquinavir and/or other drug.1518394

Drugs Affecting or Affected by P-gp Transport

Potential pharmacokinetic interaction with drugs that are inhibitors, inducers, or substrates of P-gp with possible alteration in pharmacokinetics of saquinavir and/or other drug.1

Drugs that Prolong the QT or PR Interval

Dose-dependent prolongation of QT and PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir; additive effects on QT and/or PR interval prolongation may occur if ritonavir-boosted saquinavir is used concomitantly with other drugs known to have similar effects.1 Concomitant use with other drugs known to prolong QT and/or PR intervals (e.g., class IA and class III antiarrhythmic agents, neuroleptics, phosphodiesterase type 5 inhibitors if used for PAH, some antidepressants, some anti-infectives, some antihistamines) not recommended.1119 (See Cardiovascular Effects under Cautions.)

Rifabutin: If used with ritonavir-boosted saquinavir, increased concentrations of rifabutin and its active metabolite;196 slightly decreased saquinavir concentrations;196 no change in ritonavir concentrations96

Bedaquiline: Use concomitantly with ritonavir-boosted saquinavir with caution and only if potential benefits outweigh risks;200 monitor for QTc interval prolongation and liver dysfunction200

Rifabutin: If used concomitantly with ritonavir-boosted saquinavir, saquinavir manufacturer states use usual dosage of ritonavir-boosted saquinavir and decrease rifabutin dosage by at least 75% (i.e., maximum rifabutin dosage of 150 mg every other day or 150 mg 3 times weekly);1 some experts recommend rifabutin dosage of 150 mg once daily or 300 mg 3 times weekly;200 increase monitoring for antimycobacterial effects and adverse events196200 and consider monitoring plasma rifabutin concentrations1200

Parenteral midazolam: Experts state that a single parenteral midazolam dose can be given with caution in a monitored situation for procedural sedation in patients receiving ritonavir-boosted saquinavir;200 manufacturer states patient should be monitored closely for respiratory depression and/or prolonged sedation and dosage adjustment considered1

In patients already receiving ritonavir-boosted saquinavir for ≥10 days, initiate bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1200

In patients receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted saquinavir; after ≥10 days of ritonavir-boosted saquinavir, resume bosentan using a dosage of 62.5 mg once daily or every other day based on individual tolerability1200

Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted saquinavir1

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted saquinavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1200

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted saquinavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1200

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted saquinavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1200

Budesonide or fluticasone (orally inhaled, intranasal): Do not use concomitantly unless potential benefits of intranasal or inhaled corticosteroid outweigh risks of systemic corticosteroid adverse effects;1200 consider alternative (e.g., beclomethasone);200 if concomitant use with fluticasone necessary, reduce fluticasone dosage and monitor for local and systemic effects1

Methylprednisolone, prednisolone, triamcinolone (intra-articular or other local injections): Do not use concomitantly; consider alternative nonsteroidal therapies; if intra-articular corticosteroid required, use alternative antiretroviral that does not alter CYP3A activity (e.g., dolutegravir, raltegravir)200

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving saquinavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Concomitant use of ledipasvir/sofosbuvir and HIV antiretroviral regimen that includes ritonavir-boosted saquinavir and tenofovir DF: Experts state consider alternative HCV treatment or an alternative antiretroviral regimen;200 if concomitant use necessary, monitor for tenofovir-associated adverse effects200

Tadalafil for treatment of erectile dysfunction: Use initial tadalafil dosage of 5 mg; do not exceed a single dose of 10 mg in 72 hours; monitor closely for adverse effects1200

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200

Tadalafil (Adcirca) for treatment of PAH: In patients already receiving ritonavir-boosted saquinavir for ≥1 week, use initial tadalafil dosage of 20 mg once daily and increase dosage to 40 mg once daily based on individual tolerability1200

Avoid use of tadalafil (Adcirca) for treatment of PAH during initiation of ritonavir-boosted saquinavir therapy;1200 in patients receiving tadalafil for treatment of PAH, discontinue tadalafil for at least 24 hours before starting ritonavir-boosted saquinavir; tadalafil can be restarted after ≥1 week of ritonavir-boosted saquinavir therapy using initial tadalafil dosage of 20 mg once daily and increasing dosage to 40 mg once daily based on individual tolerability1200

If tadalafil is used for treatment of benign prostatic hyperplasia, do not exceed tadalafil dosage of 2.5 mg once daily200

Tenofovir

No clinically important change in saquinavir or tenofovir concentrations or AUC with saquinavir 1 g twice daily and ritonavir 100 mg twice daily with tenofovir 300 mg once daily1221

In vitro evidence of additive or synergistic antiretroviral effects against HIV-1221

Saquinavir Pharmacokinetics

Absorption

Bioavailability

When used with low-dose ritonavir (ritonavir-boosted saquinavir), there is a 5-fold increase in mean saquinavir AUC, increases of a similar magnitude in trough and peak plasma concentrations, and less interindividual variability in saquinavir pharmacokinetics compared with saquinavir without ritonavir.174192

When low initial dosage of ritonavir-boosted saquinavir (saquinavir 500 mg twice daily with ritonavir 100 mg twice daily) for the first 7 days of therapy used in treatment-naive HIV-infected patients, saquinavir systemic exposures on day 3 are approximately 70% lower compared with exposures on day 3 in healthy adults receiving the usually recommended dosage (saquinavir 1 g twice daily with ritonavir 100 mg twice daily).1

Limited data from pediatric patients 4 months to <16 years of age who received saquinavir 50 mg/kg twice daily (up to 1 g twice daily) in conjunction with low-dose ritonavir or lopinavir/ritonavir indicate saquinavir plasma concentrations may be substantially higher in this age group than those reported in adults receiving usual saquinavir dosage; in some cases, steady-state exposures were substantially higher than those historically associated with QTc and PR interval prolongation in adults.1

Advice to Patients

Saquinavir medication guide must be provided to the patient each time the drug is dispensed;1 importance of patient reading the medication guide prior to initiating saquinavir therapy and each time prescription is refilled.1

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

Importance of using in conjunction with other antiretrovirals—not for monotherapy.1

Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.203

Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1200

Importance of taking within 2 hours of a meal, not on an empty stomach.1

Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

161. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors of NNRTI. MMWR Morb Mortal Wkly Rep. 2000; 49:185-9. http://www.ncbi.nlm.nih.gov/pubmed/11795500?dopt=AbstractPlus

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (April 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (October 26, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov